{"title":"糖原合成酶激酶-3 β在胃泌素诱导的胃癌细胞迁移过程中调控蜗牛蛋白和β -连环蛋白。","authors":"Prajna Mishra, Subramanian Senthivinayagam, Ajay Rana, Basabi Rana","doi":"10.1186/1750-2187-5-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The gastrointestinal peptide hormone gastrin is known to regulate various cellular processes including proliferation, migration and metastasis in gastrointestinal (GI) cells. The studies described here were undertaken to elucidate in detail the signaling pathways mediating the migratory responses of amidated gastrin (G17) and to understand the involvement of the serine/threonine kinase Glycogen Synthase Kinase-3 beta (GSK3beta) in this.</p><p><strong>Results: </strong>Our results indicate that incubation of gastric cancer cells overexpressing CCK2 receptor (AGSE cells) with G17 results in a dose and time dependent increase of GSK3betaSer9 phosphorylation, indicative of an inhibition of the kinase. Pretreatment with a pharmacological inhibitor of PI3Kinase pathway (Wortmannin) was unable to antagonize G17-induced GSK3betaSer9 phosphorylation, suggesting that this might involve PI3Kinase-independent pathways. Treatment with G17 was also associated with increased Snail expression, and beta-catenin nuclear translocation, both of which are GSK3beta downstream targets. Pretreatment with a pharmacological inhibitor of GSK3beta (AR-A014418) augmented Snail expression and beta-catenin nuclear translocation in the absence of G17, whereas overexpression of a phosphorylation deficient mutant of GSK3beta (S9A) abrogated Snail promoter induction. These suggested that G17 modulates Snail and beta-catenin pathways via inhibiting GSK3beta. In addition, overexpression of GSK3beta wild type (WT) or S9A mutant inhibited G17-induced migration and MMP7 promoter induction. G17 studies designed following small interference RNA (siRNA)-mediated knockdown of Snail and beta-catenin expression indicated a significant reduction of G-17-induced migration and MMP7 promoter induction following combined knockdown of both proteins.</p><p><strong>Conclusion: </strong>Our studies indicate that inhibition of GSK3beta is necessary to activate G17-induced migratory pathways in gastric cancer cells. Inhibition of GSK3beta leads to an induction of Snail expression and beta-catenin nuclear translocation, both of which participate to promote G17-induced migration.</p>","PeriodicalId":35051,"journal":{"name":"Journal of Molecular Signaling","volume":"5 ","pages":"9"},"PeriodicalIF":0.0000,"publicationDate":"2010-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1750-2187-5-9","citationCount":"35","resultStr":"{\"title\":\"Glycogen Synthase Kinase-3beta regulates Snail and beta-catenin during gastrin-induced migration of gastric cancer cells.\",\"authors\":\"Prajna Mishra, Subramanian Senthivinayagam, Ajay Rana, Basabi Rana\",\"doi\":\"10.1186/1750-2187-5-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The gastrointestinal peptide hormone gastrin is known to regulate various cellular processes including proliferation, migration and metastasis in gastrointestinal (GI) cells. The studies described here were undertaken to elucidate in detail the signaling pathways mediating the migratory responses of amidated gastrin (G17) and to understand the involvement of the serine/threonine kinase Glycogen Synthase Kinase-3 beta (GSK3beta) in this.</p><p><strong>Results: </strong>Our results indicate that incubation of gastric cancer cells overexpressing CCK2 receptor (AGSE cells) with G17 results in a dose and time dependent increase of GSK3betaSer9 phosphorylation, indicative of an inhibition of the kinase. Pretreatment with a pharmacological inhibitor of PI3Kinase pathway (Wortmannin) was unable to antagonize G17-induced GSK3betaSer9 phosphorylation, suggesting that this might involve PI3Kinase-independent pathways. Treatment with G17 was also associated with increased Snail expression, and beta-catenin nuclear translocation, both of which are GSK3beta downstream targets. Pretreatment with a pharmacological inhibitor of GSK3beta (AR-A014418) augmented Snail expression and beta-catenin nuclear translocation in the absence of G17, whereas overexpression of a phosphorylation deficient mutant of GSK3beta (S9A) abrogated Snail promoter induction. These suggested that G17 modulates Snail and beta-catenin pathways via inhibiting GSK3beta. In addition, overexpression of GSK3beta wild type (WT) or S9A mutant inhibited G17-induced migration and MMP7 promoter induction. G17 studies designed following small interference RNA (siRNA)-mediated knockdown of Snail and beta-catenin expression indicated a significant reduction of G-17-induced migration and MMP7 promoter induction following combined knockdown of both proteins.</p><p><strong>Conclusion: </strong>Our studies indicate that inhibition of GSK3beta is necessary to activate G17-induced migratory pathways in gastric cancer cells. Inhibition of GSK3beta leads to an induction of Snail expression and beta-catenin nuclear translocation, both of which participate to promote G17-induced migration.</p>\",\"PeriodicalId\":35051,\"journal\":{\"name\":\"Journal of Molecular Signaling\",\"volume\":\"5 \",\"pages\":\"9\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2010-07-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1186/1750-2187-5-9\",\"citationCount\":\"35\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Molecular Signaling\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1186/1750-2187-5-9\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Molecular Signaling","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1186/1750-2187-5-9","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
Glycogen Synthase Kinase-3beta regulates Snail and beta-catenin during gastrin-induced migration of gastric cancer cells.
Background: The gastrointestinal peptide hormone gastrin is known to regulate various cellular processes including proliferation, migration and metastasis in gastrointestinal (GI) cells. The studies described here were undertaken to elucidate in detail the signaling pathways mediating the migratory responses of amidated gastrin (G17) and to understand the involvement of the serine/threonine kinase Glycogen Synthase Kinase-3 beta (GSK3beta) in this.
Results: Our results indicate that incubation of gastric cancer cells overexpressing CCK2 receptor (AGSE cells) with G17 results in a dose and time dependent increase of GSK3betaSer9 phosphorylation, indicative of an inhibition of the kinase. Pretreatment with a pharmacological inhibitor of PI3Kinase pathway (Wortmannin) was unable to antagonize G17-induced GSK3betaSer9 phosphorylation, suggesting that this might involve PI3Kinase-independent pathways. Treatment with G17 was also associated with increased Snail expression, and beta-catenin nuclear translocation, both of which are GSK3beta downstream targets. Pretreatment with a pharmacological inhibitor of GSK3beta (AR-A014418) augmented Snail expression and beta-catenin nuclear translocation in the absence of G17, whereas overexpression of a phosphorylation deficient mutant of GSK3beta (S9A) abrogated Snail promoter induction. These suggested that G17 modulates Snail and beta-catenin pathways via inhibiting GSK3beta. In addition, overexpression of GSK3beta wild type (WT) or S9A mutant inhibited G17-induced migration and MMP7 promoter induction. G17 studies designed following small interference RNA (siRNA)-mediated knockdown of Snail and beta-catenin expression indicated a significant reduction of G-17-induced migration and MMP7 promoter induction following combined knockdown of both proteins.
Conclusion: Our studies indicate that inhibition of GSK3beta is necessary to activate G17-induced migratory pathways in gastric cancer cells. Inhibition of GSK3beta leads to an induction of Snail expression and beta-catenin nuclear translocation, both of which participate to promote G17-induced migration.
期刊介绍：
Journal of Molecular Signaling is an open access, peer-reviewed online journal that encompasses all aspects of molecular signaling. Molecular signaling is an exponentially growing field that encompasses different molecular aspects of cell signaling underlying normal and pathological conditions. Specifically, the research area of the journal is on the normal or aberrant molecular mechanisms involving receptors, G-proteins, kinases, phosphatases, and transcription factors in regulating cell proliferation, differentiation, apoptosis, and oncogenesis in mammalian cells. This area also covers the genetic and epigenetic changes that modulate the signaling properties of cells and the resultant physiological conditions.
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